Lassa Fever, Marburg and Ebola Virus

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Lassa Fever, Marburg and Ebola Virus

In this article

Lassa fever, Marburg virus disease and Ebola virus disease are all viral haemorrhagic fevers. The reservoirs of all three diseases are mainly confined to Equatorial Africa. However, their contagiousness means that the potential for outbreak is real if imported cases go undetected. it is important, therefore, to be aware of them and to understand the conditions which create the potential for epidemic spread. Viral haemorrhagic fevers (VHFs) should be in the differential diagnosis of all travellers with unexplained pyrexia returning from an affected area. They should rise very high on the list of possibilities if there are features suggesting bleeding, hypovolaemia, increased vascular permeability, or organ failure. This is particularly important in the case of Lassa fever (LF), given the very high incidence of new infections in endemic areas. See separate Viral Haemorrhagic Fevers article.

Marburg and Ebola viruses are regarded as potential bioterrorism weapons, although it is difficult to envisage how they could be used without ultimately affecting combatants and civilians on both sides of a conflict.

Suspected VHF is a medical and public health emergency and immediate advice should be sought from the local Communicable Disease Consultant on how to proceed[1].

Pathophysiology

Causative agents

The virus family Filoviridae includes three genera: Cuevavirus, Marburgvirus and Ebolavirus.

Five species of Ebola virus have been identified: Zaire, Bundibugyo, Sudan, Reston and Taï Forest. The first three have been associated with large outbreaks in Africa. The virus causing the 2014-2016 West African outbreak was the Zaire species.

Two slightly different Marburg viruses have been demonstrated, named MARV and Ravn. Both were identified during the largest outbreak to date. The relative contribution of each virus to the outbreak was never established.

LF is the most common of the arenavirus human pathogens. Others include Argentine haemorrhagic fever (HF), Bolivian HF, Brazilian HF and Venezuelan HF.

Pathogen emergence

VHFs are emerging diseases, which made the species leap relatively recently in evolutionary terms (for comparison, tuberculosis is thought to have been a human pathogen for as long as mankind has existed, learning to adopt a slow and indolent, sometimes dormant, approach). Diseases new to mankind often have a relatively dramatic and lethal course.

LF was first described in the 1950s; the virus causing Lassa disease was not identified until 1969, when it appeared in Lassa in Nigeria. Genetic analysis suggests its presence as a pathogen in rats for a thousand years.

Marburg virus disease (MVD) - also called Marburg haemorrhagic fever (MHF) - was first recognised in 1967, when HF outbreaks occurred simultaneously in laboratories in Marburg, Frankfurt and Belgrade. Thirty-one people became ill, initially laboratory workers, followed by medical personnel and family members. Seven died. The first infected had been exposed to African green monkeys during research.

Ebola virus disease (EVD) - also called Ebola haemorrhagic fever (EHF) - first appeared in 1976 in two simultaneous outbreaks - one in Nzara (now South Sudan) and the other in Yambuku, the Democratic Republic of the Congo (formerly Zaire), in a village near the Ebola River.

Reservoirs and transmission

Lassa fever (LF)

The natural reservoir of LF is the multimammate rat, one of the most common rodents in West and Equatorial Africa.

Rodents have persistent asymptomatic infection. The virus is shed in urine and faeces, which can be aerosolised and inhaled. Inhalation is believed to be the most significant means of exposure, although gastrointestinal ingestion can also occur.

Infection is also acquired through broken skin or mucous membranes that are directly exposed to infective material.

In some Lassa endemic regions, rats are consumed, which can lead to infection.

The virus can be transmitted between infected people and animals by insect bites.

LF is highly contagious. Medical staff are at high risk of catching it from patients. Up to 300,000 infections and 5,000 deaths from LF are estimated to occur yearly, mostly in Sierra Leone, Liberia and Guinea[2].

Marburg virus disease (MVD)

Fruit bats of the Pteropodidae family are the natural hosts of Marburg virus.

Marburg virus is also transmitted through contact with bodily fluids of infected animals or people.

Human-to-human transmission is rapid, resulting from contact with bodily fluids.

Burial ceremonies where mourners have direct contact with the body of the deceased can play a significant role.

Transmission via infected semen can occur up to seven weeks after clinical recovery.

Transmission to healthcare workers is common.

Transmission via contaminated injection equipment or through needle-stick injuries is associated with more severe disease.

Ebola virus disease (EVD)

Fruit bats of the Pteropodidae family are thought to be the natural hosts of Ebola virus.

Ebola virus is introduced into the human population through close contact with the bodily fluids of infected animals such as primates, fruit bats, forest antelope and porcupines, found ill or dead or in the rainforest.

The 2014-2016 epidemic may have begun with a child playing in the forest who was exposed to infected fruit bat droppings.

Human-to-human transmission is rapid, resulting from contact with bodily fluids.

Burial ceremonies in which mourners have direct contact with the body of the deceased person also play a role in the transmission.

Healthcare workers have frequently been infected while treating patients with EVD.

People remain infectious as long as their blood contains the virus.

More research is needed on the risks of sexual transmission, and particularly on the prevalence of viable and transmissible virus in semen over time.

Epidemiology

These viruses represent relatively new diseases to humanity. The two main factors behind the emergence of VHFs are expansion of the human population and globalisation of trade. Current global issues such as the increasing movement of a variety of animal species, ecological disruption, mass migration, and bioterrorism, continue to create the conditions for spread[3].

Epidemics and endemicity

There are believed to be 300,000-500,000 new cases per year, of which around 5,000 (1-2%) are fatal.

The incidence of seroconversion in endemic regions, is from 5-20% of the non-immune population per year

The seroprevalence of LF-specific antibodies in the general population residing in the endemic regions varies from 2-55% in some areas.

Most cases are recorded in Guinea, Sierra Leone, Liberia and Nigeria.

LF has become endemic in Benin, Ghana, Guinea and Mali, possibly within a period of five years. Seropositivity has also been found in the Central African Republic, the Democratic Republic of the Congo and Senegal.

Increase in international travel and the possibility of Lassa virus being used as a bioterror weapon increases the potential for harm beyond the endemic regions.

In 2016 the 'Lassa season' generated more cases than usual, with a case mortality unusually above 50%. The World Health Organization (WHO) was notified of 273 cases, including 149 deaths in Nigeria. This may be partly due to better detection but genetic sequencing showed a new lineage of the Lassa virus.

Increasing outbreaks may also be due to increasing urbanisation and to climatic conditions favouring the rat[5].

MVD is a much rarer disease than either LF or EVD . It is included here because of its clinical similarity to EVD.

Most outbreaks of MVD have been in single figures. Sporadic outbreaks have occurred since the 1967 outbreak.

Since 1967 only two outbreaks of significant size have occurred, each with higher than usual mortality: in the Angolan outbreak of 2004-2005, 252 cases were recorded (of whom 83% died). A highly lethal outbreak amongst gold miners in the Democratic Republic of the Congo in 1998-2000 infected 154 people, also killing 83%.

Prior to the 2014-2016 West African Ebola epidemic, outbreaks of EVD primarily occurred in remote villages close to tropical rainforests in Equatorial Africa.

Confirmed cases had been reported in the Democratic Republic of the Congo, Sudan, Gabon, Uganda, the Republic of the Congo and the Côte d'Ivoire.

The 2014-2016 EVD epidemic in West Africa infected over 26,000 people, of whom around 40% died. This was the largest EVD epidemic the world had seen and the first significant outbreak in West Africa[10].

The West African 2014-2016 EVD epidemic probably began with a single individual exposed to insect-eating bats. WHO analysis of why an outbreak grew to epidemic proportions makes informative reading to those concerned about containment of epidemic VHF.

Countries in Equatorial Africa have experienced EVD outbreaks for four decades.

All previous outbreaks were controlled within three months, with fatalities in the hundreds at worst because Equatorial Africa was well informed and prepared.

Clinicians suspect EVD when a 'mysterious' disease occurs.

Laboratory capacity is in place and staff know where to send samples for rapid diagnosis.

Governments treat a confirmed case as an immediate national emergency.

West African countries had never experienced an EVD outbreak and were ill-prepared for this unfamiliar and unexpected disease.

Clinicians had never managed cases.

No laboratory had ever diagnosed a patient specimen. No government had witnessed the upheaval of an outbreak.

Populations did not understand it.

The most severely affected countries, Guinea, Liberia and Sierra Leone, had weak health systems, lacked human and infrastructural resources and had only recently emerged from long periods of conflict and instability.

Ebola virus was thus an old disease in a new context that favoured rapid and initially invisible spread.

As a result of these and other factors, the virus behaved differently in West Africa than in equatorial Africa.

Pathophysiology

The three viruses are intracellular pathogens capable of infecting many different cell types.

The initial stage of viraemia affects the vascular system, causing flushing, conjunctival injection and petechial haemorrhages, often with fever and myalgia.

Viraemia may be overwhelming if there is inadequate or delayed immune response.

The central pathological process in severe disease is the development of increased vascular permeability, with or without coagulopathy.

Central to LF pathogenesis in severe cases is failure to develop the cellular immune response that would control dissemination and replication of the virus. However, the mechanism of disease progression is not clearly understood.

One theory is that catastrophic effects result from infection-triggered induction of uncontrolled cytokine expression similar to that seen in sepsis. Another is that virus-induced immunosuppression is involved. Both of these processes occur in EVD.

Monocytes, macrophages, and dendritic cells are the preferred replication sites for filoviruses on initial infection.

Infected cells migrate to the regional lymph nodes, the liver and the spleen, disseminating the infection. Ebola virus is able to infect a variety of different cell types but extensive viral replication occurs in lymphoid tissue, the liver and the spleen.

Ebola virus has the ability to modulate the expression of genes involved in the host immune response, causing lymphocyte apoptosis and attenuation of the protective effects of interferon[13].

The host immune response dictates the outcome of infection.

Progression to the severe end of the disease spectrum occurs when the virus triggers expression of a host of pro-inflammatory cytokines, including: interferons, interleukins and tumour necrosis factor (TNF)-alpha. This, in turn, affects vascular integrity and triggers coagulopathy and increased nitric oxide levels (with associated hypotension).

The case-fatality rate for the larger outbreaks of MVD has been around 80%. The fatality rate for isolated cases is very high, due to late recognition. The fatality rate for infections acquired by needlestick injury is also very high.

Recovery from severe VHFs depends on good supportive care and the patient's immune response.

Secondary prevention requires total isolation of affected patients. Personal protective equipment must be worn and regularly checked. Meticulous infection control procedures are essential.

Drug treatments

Analgesics and antipyretics may be required. Avoid aspirin and intramuscular (IM) injections because of bleeding.

Only LF currently has an established antiviral treatment.

Despite frantic searching, no effective antiviral was found during the 2014-2016 EVD crisis. This was despite some relaxation of the requirements for normal drug trial protocols.

Drugs which have been suggested

Lassa fever (LF)The antiviral drug ribavirin seems to be an effective treatment for LF if given early on in the course of clinical illness. There is no evidence to support the role of ribavirin as post-exposure prophylactic treatment for LF[17].

The EVD outbreak of 2014-2016 led to intense global concentration on a treatment solution. In the absence of an approved treatment, experimental drugs were used in the field, under compassionate grounds. As more data were collected, Phase II/III clinical trials were introduced in Guinea, Sierra Leone and Liberia to test promising candidates, including small-molecule drugs, RNA-based treatments and antibody-based therapies[16].

The US Food and Drug Administration (FDA) allowed two drugs, ZMapp and an RNA interference drug called TKM-Ebola, to be used by two American health workers who had contracted EVD[18].

ZMapp:

ZMapp had been shown to provide a survival benefit in non-human primates experimentally infected with the virus, even when they had developed advanced disease.

ZMapp comprises three chimeric monoclonal antibodies that provide passive immunity to the virus by directly and specifically reacting with it in a 'lock and key' fashion.

During 2014, a limited supply of ZMapp was used to treat seven individuals infected with the Ebola virus; of these, two died. Mapp announced in August 2014 that supplies of ZMapp were exhausted.

There was controversy around the fact that the drug was first given to Americans and a European and not to Africans. Conversely, ethical questions were also asked about the meaning of informed consent in using the drug on seriously ill individuals unfamiliar with the context of Western medicine and an in-tried drug[16].

A randomised controlled trial (RCT) in 71 patients in 2015 concluded that although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the pre-specified statistical threshold for efficacy[20].

A few weeks after the first compassionate administration of ZMapp, a WHO panel agreed that amending traditional regulation and governance pathways for emergency drug use and development could be acceptable on specific ethical and evidential grounds. They promoted the fast-track clinical progression of many treatments, and the use of a placebo control arm to meet 'gold-standard' RCT criteria was revised. Phase II/III clinical trials began in Liberia, Sierra Leone and Guinea.

TKM-Ebola:

This a mixture of three lipid nanoparticle-encapsulated small interfering RNAs (siRNAs) that disrupt viral replication, transcription, assembly and evasion of host immune responses. The Phase I trial for TKM-Ebola was put on hold due to high cytokine release in participants. Two patients received it with convalescent plasma transfusions. There were concerns that it contributed to the overall health decline of one of the patients, who nevertheless survived. In March 2015 an open-label, non-randomised Phase II clinical trial was initiated to assess the impact of treatment. The study was halted in June 2015 due to a reported lack of apparent overall therapeutic benefit to patients.

Favipiravir:

This antiviral drug, developed for treatment of severe influenza, was one of several trialled during the outbreak after WHO recommended it amongst several drugs suitable for EVD research. In the context of the outbreak, randomising patients to receive either standard care or standard care plus an experimental drug was not felt appropriate. A non-randomised trial reached no clear conclusions but suggested that favipiravir monotherapy merited further study. Some anecdotal cases in which the drug was given together with plasma or ZMapp drugs suggested a survival benefit[21].

Convalescent plasma:

Treatment using plasma from EVD survivors with unknown antibody levels was evaluated in Guinea; however, it did not improve survival[22].

Other drugs which were tested but did not show benefit included amiodarone (which had demonstrated in-vitro antiviral activity) and brincidofovir. Neither of these showed evidence of clinical benefit in humans.

Risk factors

These include:

Living in or visiting an endemic area.

Exposure to infected people or materials.

Exposure to infected corpses, human or otherwise.

Exposure to the vector.

Infection control

Patients with suspected contagious VHF require barrier nursing. Visitors should be restricted. A sudden, large number of simultaneous cases would raise the suspicion of bioterrorism. Laboratory specimens need to be handled with extreme care.

Prognosis

For all these three viruses, severe disease is frequently fatal. Overall (all-case) mortality is generally higher for MVD and EVD than it is for LF.

Mortality rates have varied between epidemics.

Lassa fever (LF)

Figures for the mortality of LF vary, as a large number of mild or asymptomatic cases go undiagnosed. It is probably around 1%.

More meaningful is the mortality of the 20% of patients who present with severe disease. Around 15% of these patients die.

Deafness occurs in 25% of patients who survive severe disease. In half of these, hearing returns partially. Hair loss and gait disturbance may occur during recovery.

After recovery, the virus remains in body fluids for long periods of time. It is excreted in urine for three to nine weeks after infection and in semen for up to three months.

Marburg virus disease (MVD)

The mortality of MVD has been around 80%, although confirmed case numbers are relatively small. There is little available information on long-term complications.

Ebola virus disease (EVD)

The West African 2014-2016 outbreak of EVD had an overall mortality of around 40%.

Recovery from EVD may be followed by relapse.

Sequelae of EVD can be severe, such as arthritis and vision-threatening uveitis[8].

The mental health effects on survivors are profound.

Ebola virus may persist for many weeks in selected body compartments of survivors, most notably in the semen of men, bringing risk of renewed transmission where it has previously been eliminated[23].

Survivors of Ebola virus infection develop antibodies that last for at least 10 years. It is not known if people who recover are immune for life or if they can become infected with a different species of Ebola.

Prevention

The WHO has stated that the best way to prepare for an epidemic is to strengthen vaccination campaigns, to have an effective disease surveillance system, to be able to dispatch emergency workers and stockpiled vaccines quickly and to have a legitimate way to guarantee the safety and health of health workers themselves (this latter was one of the early barriers to effective containment of the West African EVD epidemic)[24].

Vector control

Control programmes for rodents and mosquitoes are required in endemic areas[25].

Prevention of LF relies on promoting good 'community hygiene' to discourage rodents from entering homes. Effective measures include storing grain and other foodstuffs in rodent-proof containers, disposing of garbage far from the home, maintaining clean households and keeping cats.

Because the rodents are so abundant, it is not possible to eliminate them from the environment[17].

Reducing the risk of wildlife-to-human transmission from contact with infected fruit bats or primates and the consumption of their raw meat: animals should be handled with gloves; animal products should be thoroughly cooked before consumption.

Raising awareness both of risk factors for Ebola virus infection, and of protective measures that individuals can take, is an effective way to reduce human transmission.

Reducing the risk of human-to-human transmission from direct or close contact with people with EVD symptoms, particularly with their bodily fluids, with appropriate personal protective equipment.

Reducing the risk of possible sexual transmission: the WHO recommends that male survivors of EVD practise safe sex for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus.

Outbreak containment measures, including prompt and safe burial of the dead, identifying people who may have been in contact with someone infected with Ebola virus, and separating the healthy from the sick to prevent further spread.

The importance of good hygiene and maintaining a clean environment.

System preparation

This requires adequate training of healthcare workers in diagnostics, intensive care of patients under isolation, contact tracing, adequate precautionary measures in handling infectious laboratory specimens, control of the vector and care and disposal of infectious waste[26].

In healthcare settings, staff should always apply infection prevention and control precautions when caring for patients, regardless of their presumed diagnosis. These include use of adequate personal protective equipment.

Healthcare workers caring for patients with suspected or confirmed LF should apply extra infection control measures.

Laboratory workers are also at risk. Samples should be processed in suitably equipped laboratories under maximum biological containment conditions.

Vaccination

Ebola virus vaccination became a priority during the most recent outbreak and advances were made[27]:

Several vaccine candidates have been developed and evaluated through clinical trials. Among them, the recombinant vesicular stomatitis virus-based vaccine (rVSV-EBOV) is the most promising candidate, demonstrating a significant protection against EVD in a Phase III clinical trial. However, several concerns were still associated with the Ebola vaccine candidates, including the safety profile, the immunisation schedule for emergency vaccination, and the persistence of the protection.

No licensed vaccines are available yet; however, two potential vaccines are undergoing human safety testing.

There are no vaccines against LF or Marburg virus.

Surveillance

Computer models using variables such as rainfall and temperature have been used to predict likely risk areas for LF in West Africa[28].

Early detection

The ability to make rapid diagnosis depends on investment in laboratory services and disease surveillance[29].

Case containment

Rapid detection and isolation of confirmed cases reduce the risk of outbreak and epidemic.

When treating patients, adequate personal prevention equipment is needed, as infection acquired from patients seems to be particularly virulent.

There should be close surveillance of contacts for three weeks, with isolation of those who become pyrexial.

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